The copy number status (CNS) of the survival motor neuron (SMN) gene may influence the risk and prognosis of amyotrophic lateral sclerosis (ALS) and lower motor neuron diseases (LMND) other than spinal muscular atrophy (SMA). However, previous studies of this association, mainly from Europe, have yielded controversial results, suggesting possible regional differences. Here, we investigated the effect of the SMN gene in Japanese patients with ALS and LMND. We examined the SMN copy numbers and clinical histories of 487 Japanese patients with sporadic ALS (281 men; mean age at onset 61.5 years), 50 with adult LMND (50 men; mean age at onset 58.4 years) and 399 Japanese controls (171 men; mean age 62.2 years). Patients with pathogenic mutations in ALS-causing genes were excluded. SMN1 and SMN2 copy numbers were determined using the droplet digital polymerase chain reaction. The frequency of a copy number of one for the SMN2 gene was higher in patients with ALS (38.0%) than in healthy controls (30.8%) (odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.04–1.82, p < 0.05). The SMN2 copy number affected the survival time of patients with ALS (median time: 0 copies, 34 months; 1 copy, 39 months; 2 copies, 44 months; 3 copies, 54 months; log-rank test, p < 0.05). Cox regression analysis revealed that the SMN2 copy number was associated with increased mortality (hazard ratio = 0.84, 95% CI = 0.72–0.98, p < 0.05). Also, null SMN2 cases were significantly more frequent in the LMND group (12.0%) than in the control group (4.8%) (OR = 2.73, 95% CI = 1.06–6.98, p < 0.05). Our findings suggest that SMN2 copy number reduction may adversely affect the onset and prognosis of MND, including ALS and LMND, in Japanese.
OBJECTIVES: STMN1 (stathmin or oncoprotein-18) destabilizes microtubules and reorganizes cytoskeleton, and functions in cell cycle progression and cell migration. STMN1 activity is influenced by p53, p27, and the PI3K/AKT pathway. However, its prognostic significance in colon cancer is uncertain. METHODS: Utilizing 546 colorectal cancers (stage I-IV) from two independent prospective cohort studies (the Nurses' Health Study and Health Professionals Follow-up Study), STMN1 expression was detected in 297 (54%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HRs) of mortality, adjusted for clinical and tumoral features, including microsatellite instability (MSI), CpG island methylation phenotype (CIMP), LINE-1 hypomethylation,KRAS, BRAF,PIK3CA, p53, p21, p27, cyclin D1, β-catenin, fatty acid synthase, FASN, and COX-2. RESULTS: Five-year colorectal cancer-specific survival was 78% in STMN1-positive patients and 76% in STMN1-negative patients (log-rankP=0.30). STMN1-positivity was not significantly associated with cancer-specific survival in univariate analysis with HR of 0.82 (95% confidence interval (CI), 0.59-1.14), which became significant in multivariate analysis (adjusted HR=0.60; 95% CI, 0.41-0.87;P= 0.0078). Notably, the prognostic effect of obesity (body mass index, BMI≥30 kg/m2) significantly differed by STMN1 (Pinteraction=0.005). Obesity was associated with high cancer-specific mortality among STMN1-positive patients (adjusted HR = 2.36; 95% CI, 1.18-4.69), whereas obesity was not associated with high mortality among STMN1-negative patients (adjusted HR =0.51; 95% CI, 0.24-1.07). CONCLUSIONS: STMN1 overexpression in colorectal cancer is independently associated with improved survival. The adverse prognostic effect of obesity was limited to patients with STMN1-positive tumors. Our findings suggest the presence of a tumor (STMN1)-host (BMI) interaction that potentially determines clinical outcome.
Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1 can be blocked by CDK inhibitors, including p27 (CDKN1B) and p21 (CDKN1A, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1 hypomethylation].Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1 overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1 methylation, CpG island methylator phenotype, MSI, BMI, KRAS, and BRAF.Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (P = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; P = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% CI, 0.39-0.84; P = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% CI, 0.57-0.98; P = 0.036). Notably, the effect of cyclin D1 on survival might differ by MSI status (P(interaction) = 0.008). Compared with tumors that were both cyclin D1-negative and MSI-low/microsatellite stable, the presence of either cyclin D1 or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65).Cyclin D1 overexpression is associated with longer survival in colon cancer.
<div>Abstract<p><b>Purpose:</b> Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1 can be blocked by CDK inhibitors, including p27 (<i>CDKN1B</i>) and p21 (<i>CDKN1A</i>, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1 hypomethylation].</p><p><b>Experimental Design:</b> Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1 overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer–specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1 methylation, CpG island methylator phenotype, MSI, BMI, <i>KRAS</i>, and <i>BRAF</i>.</p><p><b>Results:</b> Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (<i>P</i> = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; <i>P</i> = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% CI, 0.39-0.84; <i>P</i> = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% CI, 0.57-0.98; <i>P</i> = 0.036). Notably, the effect of cyclin D1 on survival might differ by MSI status (<i>P</i><sub>interaction</sub> = 0.008). Compared with tumors that were both cyclin D1–negative and MSI-low/microsatellite stable, the presence of either cyclin D1 or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65).</p><p><b>Conclusions:</b> Cyclin D1 overexpression is associated with longer survival in colon cancer.</p></div>
A sedentary lifestyle with insufficient exercise is associated with cardiovascular disease. Previous studies have demonstrated that endurance exercise benefits atherosclerosis and cardiovascular disorders; however, the mechanisms by which physical activity, such as voluntary exercise (Ex), produces these effects are not fully understood.Eight-week-old male apolipoprotein (ApoE)-deficient mice were fed a standard diet (STD) or high fat diet (HFD) for 10 weeks. The HFD+Ex group mice performed Ex on a running wheel for 10 weeks. No significant differences in lipid profiles were observed between the HFD and HFD+Ex groups. Although changes in body and brown adipose tissue weights were comparable between the HFD and HFD+Ex groups, white adipose tissue weight was significantly lower in the HFD+Ex group than in the HFD group. The areas of atherosclerotic lesions in the aortic sinus and thoracoabdominal aorta were significantly reduced in the HFD+Ex group than in the HFD group (p<0.001). There was a strong negative correlation between atherosclerotic areas and the mean running distance per day in the HFD+Ex group (r=-0.90, p=0.01). Endothelial function was significantly preserved in the HFD+Ex group (p<0.05). Serum interleukin-6 and macrophage chemoattractant protein-1 levels were significantly lower and those of adiponectin were significantly higher in the HFD+Ex group than in the HFD group (p<0.05).These results suggest that Ex ameliorates the progression of endothelial dysfunction and atherosclerotic lesion formation through anti-inflammatory effects, despite continued consumption of HFD.
AURKA (the official symbol for Aurora-A, STK15, or BTAK) regulates the function of centrosomes, spindles, and kinetochores for proper mitotic progression. AURKA overexpression is observed in various cancers including colon cancer, and a link between AURKA and chromosomal instability (CIN) has been proposed. However, no study has comprehensively examined AURKA expression in relation to CIN or prognosis using a large number of tumors. Using 517 colorectal cancers in two prospective cohort studies, we detected AURKA overexpression (by immunohistochemistry) in 98 tumors (19%). We assessed other molecular events including loss of heterozygosity (LOH) in 2p, 5q, 17q, and 18q, the CpG island methylation phenotype (CIMP), and microsatellite instability (MSI). Prognostic significance of AURKA was evaluated by Cox regression and Kaplan-Meier method. In both univariate and multivariate logistic regressions, AURKA overexpression was significantly associated with CIN (defined as the presence of LOH in any of the chromosomal segments; multivariate odds ratio, 2.97; 95% confidence interval, 1.40–6.29; P = .0045). In multivariate analysis, AURKA was associated with cyclin D1 expression (P = .010) and inversely with PIK3CA mutation (P=.014), fatty acid synthase expression (P=.028), and family history of colorectal cancer (P = .050), but not with sex, age, body mass index, tumor location, stage, CIMP, MSI, KRAS, BRAF, BMI, LINE-1 hypomethylation, p53, p21, β-catenin, or cyclooxygenase 2. AURKA was not significantly associated with clinical outcome or survival. In conclusion, AURKA overexpression is independently associated with CIN in colorectal cancer, supporting a potential role of Aurora kinase-A in colorectal carcinogenesis through genomic instability (rather than epigenomic instability).
<div>Abstract<p><b>Purpose:</b> Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1 can be blocked by CDK inhibitors, including p27 (<i>CDKN1B</i>) and p21 (<i>CDKN1A</i>, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1 hypomethylation].</p><p><b>Experimental Design:</b> Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1 overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer–specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1 methylation, CpG island methylator phenotype, MSI, BMI, <i>KRAS</i>, and <i>BRAF</i>.</p><p><b>Results:</b> Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (<i>P</i> = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; <i>P</i> = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% CI, 0.39-0.84; <i>P</i> = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% CI, 0.57-0.98; <i>P</i> = 0.036). Notably, the effect of cyclin D1 on survival might differ by MSI status (<i>P</i><sub>interaction</sub> = 0.008). Compared with tumors that were both cyclin D1–negative and MSI-low/microsatellite stable, the presence of either cyclin D1 or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65).</p><p><b>Conclusions:</b> Cyclin D1 overexpression is associated with longer survival in colon cancer.</p></div>
